Genetic Variant CALHM6:p.Arg144Ser (chr6-116462359-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001010919.3(CALHM6):c.430C>A(p.Arg144Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,448,956 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00095 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 1 hom. )

Consequence

CALHM6
NM_001010919.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.345

Variant links:

Genes affected

CALHM6 (HGNC:33391): (calcium homeostasis modulator family member 6) Predicted to enable cation channel activity. Predicted to be involved in cation transmembrane transport. Predicted to be integral component of membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CALHM6 links:

ENSG00000285446 (HGNC:):

ENSG00000285446 links:

CALHM6-AS1 (HGNC:40971): (CALHM6 antisense RNA 1)

CALHM6-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0068805516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM6	NM_001010919.3 link	c.430C>A	p.Arg144Ser	missense_variant	Exon 2 of 3	ENST00000368605.3	NP_001010919.1	Q5R3K3-1
CALHM6	XM_011535845.4 link	c.430C>A	p.Arg144Ser	missense_variant	Exon 1 of 2		XP_011534147.1
CALHM6	NM_001276460.2 link	c.10-924C>A		intron_variant	Intron 1 of 1		NP_001263389.1	Q5R3K3-2
CALHM6-AS1	NR_174951.1 link	n.87-1165G>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALHM6	ENST00000368605.3 link	c.430C>A	p.Arg144Ser	missense_variant	Exon 2 of 3	5	NM_001010919.3	ENSP00000357594.1		Q5R3K3-1
ENSG00000285446	ENST00000644499.1 link	c.767-924C>A		intron_variant	Intron 3 of 3			ENSP00000495266.1		A0A2R8Y6J1

Frequencies

GnomAD3 genomes

AF:

0.000953

AC:

145

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00175

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000792

AC:

AN:

56852

Hom.:

AF XY:

0.000597

AC XY:

AN XY:

33522

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000218

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000586

Gnomad NFE exome

AF:

0.00190

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00134

AC:

1740

AN:

1296670

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

804

AN XY:

637790

show subpopulations

Gnomad4 AFR exome

AF:

0.000157

Gnomad4 AMR exome

AF:

0.000245

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000499

Gnomad4 NFE exome

AF:

0.00158

Gnomad4 OTH exome

AF:

0.00126

GnomAD4 genome

AF:

0.000952

AC:

145

AN:

152286

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00175

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000842

Hom.:

Bravo

AF:

0.000918

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ExAC

AF:

0.0000892

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.430C>A (p.R144S) alteration is located in exon 2 (coding exon 1) of the FAM26F gene. This alteration results from a C to A substitution at nucleotide position 430, causing the arginine (R) at amino acid position 144 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.11

DANN

Benign

0.66

DEOGEN2

Benign

0.00057

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.29

M_CAP

Benign

0.0030

MetaRNN

Benign

0.0069

MetaSVM

Benign

-0.99

PrimateAI

Benign

0.43

PROVEAN

Benign

1.2

REVEL

Benign

0.027

Sift

Benign

1.0

Sift4G

Benign

0.82

Polyphen

0.0

Vest4

0.058

MVP

0.040

MPC

0.098

ClinPred

0.033

GERP RS

-9.4

Varity_R

0.24

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over